Tsjitske J. Toering

Body mass index and body fat distribution as renal risk factors: a focus on the role of renal haemodynamics.

Weight excess and/or central body fat distribution are associated with increased long-term renal risk, not only in subjects with renal disease or renal transplant recipients, but also in the general population. As the prevalence of weight excess is rising worldwide, this may become a main renal risk factor on a population basis, even more so because the risk extends to the overweight range. Understanding the mechanisms of this detrimental effect of weight excess on the kidneys is needed in order to design preventive treatment strategies. The increased risk associated with weight excess is partly attributed to associated comorbid conditions, such as hypertension, dyslipidaemia, insulin resistance and diabetes; however, current evidence supports a direct pathogenetic role for renal haemodynamics as well. Weight excess is associated with an altered renal haemodynamic profile, i.e. an increased glomerular filtration rate relative to effective renal plasma flow, resulting in an increased filtration fraction (FF). This renal haemodynamic profile is considered to reflect glomerular hyperfiltration and glomerular hypertension, resulting from a dysbalance between afferent and efferent arterial vasomotor balance. This unfavorable renal haemodynamic profile was found to be associated with renal outcome in experimental models and in human renal transplant recipients, and is associated with a blunted sodium excretion, and reversible by weight loss, renin-angiotensin-aldosterone system blockade or by dietary sodium restriction. More recent evidence showed that a central body fat distribution is also associated with an increased FF, even independent of overall weight excess. In this review, we provide an overview on current literature on the impact of weight excess and central body fat distribution on the renal haemodynamic profile in humans, and its possible role in progressive renal damage.

From preeclampsia to renal disease: a role of angiogenic factors and the renin-angiotensin aldosterone system?

Complicating up to 8% of pregnancies, preeclampsia is the most common glomerular disease worldwide and remains a leading cause of infant and maternal morbidity and mortality. Although the exact pathogenesis of this syndrome of hypertension and proteinuria is still incomplete, a consistent line of evidence has identified an imbalance of proangiogenic and anti-angiogenic proteins as a key factor in the development of preeclampsia. Furthermore, more attention has been recently addressed to the renin-angiotensin aldosterone system (RAAS), to provide understanding on the hypertension of preeclampsia. The imbalance of the RAAS and the imbalance between angiogenic and anti-angiogenic factors, which may be both common to preeclampsia and chronic kidney disease (CKD), might explain why a history of preeclampsia predisposes women to develop CKD. In this review, we briefly describe the characteristics of preeclampsia with a focus on the mechanisms of angiogenesis and the RAAS and its role in the pathogenesis of preeclampsia. Our main focus will be on the intriguing association between preeclampsia and the subsequent increased risk of developing CKD and on the potential mechanisms by which the risk of CKD is elevated in women with a history of preeclampsia.

Gender differences in response to acute and chronic angiotensin II infusion: a translational approach

Women with renal disease progress at a slower rate to end stage renal disease than men. As angiotensin II has both hemodynamic and direct renal effects, we hypothesized that the female protection may result from gender differences in responses to angiotensin II. Therefore, we studied gender differences in response to angiotensin II, during acute (human) and chronic (rats) angiotensin II administration. In young healthy men (n = 18) and women (n = 18) we studied the responses of renal hemodynamics (125I‐iothalamate and 131I‐Hippuran) and blood pressure to graded angiotensin II infusion (0.3, 1.0, and 3.0 ng/kg/min for 1 h). Men had increased responses of diastolic blood pressure (P = 0.01), mean arterial pressure (P = 0.05), and a more pronounced decrease in effective renal plasma flow (P = 0.009) than women. We measured the changes in proteinuria and blood pressure in response to chronic administration (200 ng/kg/min for 3 weeks) of angiotensin II in rats. Male rats had an increased response of proteinuria compared with females (GEE analysis, P = 0.001). Male, but not female, angiotensin II‐treated rats had increased numbers of renal interstitial macrophages compared to sham‐treated rats (P < 0.001). In conclusion, gender differences are present in the response to acute and chronic infusion of angiotensin II. Difference in angiotensin II sensitivity could play a role in gender differences in progression of renal disease.

Impaired sodium-dependent adaptation of arterial stiffness in formerly preeclamptic women: the RETAP-vascular study

Women with a history of preeclampsia have an increased risk for cardiovascular diseases later in life. Persistent vascular alterations in the postpartum period might contribute to this increased risk. The current study assessed arterial stiffness under low sodium (LS) and high sodium (HS) conditions in a well-characterized group of formerly early-onset preeclamptic (fPE) women and formerly pregnant (fHP) women. Eighteen fHP and 18 fPE women were studied at an average of 5 yr after pregnancy on 1 wk of LS (50 mmol Na(+)/day) and 1 wk of HS (200 mmol Na(+)/day) intake. Arterial stiffness was measured by pulse-wave analysis (aortic augmentation index, AIx) and carotid-femoral pulse-wave velocity (PWV). Circulating markers of the renin-angiotensin aldosterone system (RAAS), extracellular volume (ECV), nitric oxide (NO), and hydrogen sulfide (H2S) were measured in an effort to identify potential mechanistic elements underlying adaptation of arterial stiffness. AIx was significantly lower in fHP women on LS compared with HS while no difference in AIx was apparent in fPE women. PWV remained unchanged upon different sodium loads in either group. Comparable sodium-dependent changes in RAAS, ECV, and NO/H2S were observed in fHP and fPE women. fPE women have an impaired ability to adapt their arterial stiffness in response to changes in sodium intake, independently of blood pressure, RAAS, ECV, and NO/H2S status. The pathways involved in impaired adaptation of arterial stiffness, and its possible contribution to the increased long-term risk for cardiovascular diseases in fPE women, remain to be investigated.

Gender Differences in Renin Angiotensin Aldosterone System Affect Extra Cellular Volume in Healthy Subjects

Several studies reported sex differences in aldosterone. It is unknown whether these differences are associated with differences in volume regulation. Therefore we studied both aldosterone and extracellular volume in men and women on different sodium intakes. In healthy normotensive men ( n = 18) and premenopausal women ( n = 18) we investigated plasma aldosterone, blood pressure, and extracellular volume (125I-iothalamate), during both low (target intake 50 mmol Na+/day) and high sodium intake (target intake 200 mmol Na+/day) in a crossover setup. Furthermore, we studied the adrenal response to angiotensin II infusion (0.3, 1.0, and 3.0 ng·kg-1·min-1 for 1 h) on both sodium intakes. Men had a significantly higher plasma aldosterone, extracellular volume, and systolic blood pressure than women during high sodium intake ( P < 0.05). During low sodium intake, extracellular volume and blood pressure were higher in men as well ( P < 0.05), whereas the difference in plasma aldosterone was no longer significant ( P = 0.252). The adrenal response to exogenous angiotensin II was significantly lower in men than in women on both sodium intakes. Constitutive sex differences in the regulation of aldosterone, characterized by a higher aldosterone and a lower adrenal response to exogenous angiotensin II infusion in men, are associated with a higher extracellular volume and blood pressure in men. These findings suggest that sex differences in the regulation of aldosterone contribute to differences in volume regulation between men and women.

Angiotensin II responsiveness after preeclampsia: Translational data from an experimental rat model and early-onset human preeclampsia

Objective: Formerly preeclamptic women have an increased risk for cardiovascular and renal disease later in life. It is unknown which mechanisms contribute to this increased risk and whether this is induced by preeclampsia or by prepregnancy factors. We hypothesized that the increased risk for cardiovascular disease is partly due to an increased angiotensin II (ang II) responsiveness postpartum and that preeclampsia itself is involved in inducing this increased ang II responsiveness. Methods: In never-pregnant, formerly healthy pregnant rats and rats with former experimental preeclampsia [experimental preeclampsia model induced by low-dose endotoxin infusion on day 14 of pregnancy; endotoxin-infused pregnant rats (EP-rats)], ang II responsiveness was studied by measuring changes in blood pressure (BP) and proteinuria after chronic ang II infusion with osmotic minipumps (200 ng/kg per min). In addition, we measured BP and responses to ang II (0.3, 1.0 and 3.0 ng/kg per min) in 18 formerly early-onset preeclamptic, without comorbidities, and 18 formerly healthy pregnant women (controls). Results: In rats, a significantly higher systolic BP at termination was observed in formerly EP-rats vs. never-pregnant rats after ang II infusion (159.5 ± 29.5 vs. 136.7 ± 16.8; P = 0.049). In response to ang II, there was a significant increase in proteinuria in formerly EP-rats vs. healthy pregnant and never-pregnant rats (P < 0.01 for both). In humans, 1.0 ng/kg per min ang II showed a trend towards an increased mean arterial BP response in formerly preeclamptic women vs. controls (P = 0.057). Conclusion: Our data show an increased ang II responsiveness following (experimental) preeclampsia and support a role for preeclampsia itself in altered ang II responsiveness postpartum.

The role of the VEGF-C signaling pathway in preeclampsia?

We read with interest the review paper by Rakova et al. 2013) about novel findings in sodium metabolism, volme regulation, and the (possible) links with pregnancy nd preeclampsia. The authors review the involvement f the immune system in pregnancy and preeclampsia, ith a specific link to the novel paradigm of sodium omeostasis. Recent studies showed that sodium can be tored non-osmotically in a newly discovered subcutaeous interstitial compartment via macrophages acting s osmosensors. These macrophages activate the vascuar endothelial growth factor (VEGF)-C signaling pathway, hich subsequently modifies the lymph–capillary network n the skin and enhances production of vasodilatory nitric xide in the skin vessels via the VEGF receptors VEGFRand VEGFR-2, respectively. Indeed, human studies have hown that in healthy men and in proteinuric chronic kidey disease (CKD) patients, VEGF-C is modulated by salt ntake, with higher VEGF-C levels during high salt intake. t either high or low sodium intake VEGF-C levels were igher in the proteinuric patients, i.e., the population with alt-sensitive blood pressure and edema, with disturbed verall sodium balance, and altered volume distribution ver body compartments (Slagman et al., 2011). Rakova t al. (2013) link old literature on sodium homeostasis durng pregnancy and preeclampsia, and hypothesize that the ew sodium paradigm might be relevant to the pathogeneis of preeclampsia. Although little is known about the new odium concept in preeclamptic women, we would like to oint out that there are data available, albeit limited, on EGF-C and its signaling pathway in preeclampsia. Groten et al. (2010) have shown that VEGFR-2 expresion was significantly reduced in the syncytiotrophoblast nd endothelium of the placenta of preeclamptic women. oreover, a recent study showed reduced soluble VEGFRin preeclampsia in both plasma and placental tissue Munaut et al., 2012). With respect to the balance of EGF-C and its receptors, at a gestational age of 34 eeks, preeclamptic women have a lower soluble VEGFR+ VEGFR-2/VEGF-C ratio than normal pregnant women Lely et al., 2013), suggesting that preeclampsia may be haracterized by an enhanced lymphangiogenic state, in n interesting parallel with the observation in proteinric CKD patients. These alterations could be secondary o sodium retention in these patients, and/or be involved

Donor Kidney Adapts to Body Dimensions of Recipient

Female kidneys and kidneys from small donors have been suggested to perform worse after kidney transplantation. Here, we evaluate the impact of gender and body dimensions on posttransplantation GFR in living donor transplantation. Two hundred and ninety‐three donor–recipient pairs, who were transplanted at our center were evaluated. All pairs had detailed renal function measurement (125I‐iothalamate and 131I‐hippuran) 4 months predonation in the donor and 2.5 months posttransplantation in donor and recipient. For 88 pairs, 5 years of recipient follow‐up was available. Delta GFR was calculated as (recipient GFR–donor single kidney GFR). Recipients of both male and female kidneys had similar renal function at early and long term after transplantation. Male recipients had higher ERPF, ΔGFR and ΔERPF at both time points. Kidneys of donors smaller than their recipient had higher ΔGFR and ΔERPF than kidneys of larger donors at both time points (p < 0.05). In multivariate analysis, ΔGFR was predicted by donor/recipient BSA‐ratio together with transplantation related factors (R2 0.19), irrespective of donor and recipient gender. In conclusion, in living donor transplantation, female kidneys perform as well as male donor kidneys. Kidneys adapt to the recipients body size and demands, independent of gender, without detrimental effects in renal function and outcome up to mid‐long term.

Donor Kidney Adapts to Body Dimensions of Recipient: No Influence of Donor Gender on Renal Function After Transplantation: Kidneys Adapt to Body Size Irrespective of Gender

Female kidneys and kidneys from small donors have been suggested to perform worse after kidney transplantation. Here, we evaluate the impact of gender and body dimensions on posttransplantation GFR in living donor transplantation. Two hundred and ninety‐three donor–recipient pairs, who were transplanted at our center were evaluated. All pairs had detailed renal function measurement (125I‐iothalamate and 131I‐hippuran) 4 months predonation in the donor and 2.5 months posttransplantation in donor and recipient. For 88 pairs, 5 years of recipient follow‐up was available. Delta GFR was calculated as (recipient GFR–donor single kidney GFR). Recipients of both male and female kidneys had similar renal function at early and long term after transplantation. Male recipients had higher ERPF, ΔGFR and ΔERPF at both time points. Kidneys of donors smaller than their recipient had higher ΔGFR and ΔERPF than kidneys of larger donors at both time points (p < 0.05). In multivariate analysis, ΔGFR was predicted by donor/recipient BSA‐ratio together with transplantation related factors (R2 0.19), irrespective of donor and recipient gender. In conclusion, in living donor transplantation, female kidneys perform as well as male donor kidneys. Kidneys adapt to the recipients body size and demands, independent of gender, without detrimental effects in renal function and outcome up to mid‐long term.